- Press Release Distribution

Impact of genes linked to neurodevelopmental diseases found in Stanford Medicine-led study

Jumble of autism genes categorized

( Stanford Medicine investigators and their colleagues sifted through a jumble of genes implicated in neurodevelopmental disorders and identified dozens of disparate troublemakers with similar effects.

Because the method they used sorts defective genes by their function — or in this case, their dysfunction — the approach is likely to accelerate drug development for neurodevelopmental disorders.

Studies have implicated at least 500 genes in such disorders. But scientists have no idea exactly how defects in most of these genes impair brain function.

The research, which points the way toward creating order from this chaos, is described in a paper to be published online Sept. 27 in Nature. Sergiu Pasca, MD, the Kenneth T. Norris, Jr. Professor II of Psychiatry and Behavioral Sciences, is the study’s senior author. The lead author is Xiangling Meng, PhD, a postdoctoral scholar in Pasca’s group.

There are two main classes of neurons in the cerebral cortex: excitatory and inhibitory. Excitatory neurons fire impulses that activate other neurons, while inhibitory neurons’ firing blocks other neurons from firing. Inhibitory and excitatory neurons integrate to form circuits, shaping signaling activity in the brain.

In humans, as many as half of all cells in the cerebral cortex, the brain’s outermost and most recently evolved layer, are inhibitory. Scientists theorize that an imbalance in the number or function of inhibitory neurons compared with excitatory neurons might be at least partly responsible for autism spectrum disorder and epilepsy.

“If that’s true, you could find ways to alter the functional balance of these cells in the cortex as a therapeutic approach for these disorders,” Pasca said. But first, he wondered, how do you make sense of the enormous collection of genes that have been implicated in these conditions but whose impacts are largely unknown?

Does the existence of hundreds of genes associated with disease mean that there are hundreds of different types of neurodevelopmental disorders, each requiring a different remedy? Or might several different genes converge and lead to similar pathology, or some particular aspect of it?

“If it’s the latter, a cluster of gene defects that all produce a similar physiological deficit might be amenable to a single type of treatment,” Pasca said.

A new avenue of research

Until recently, there was no way to study early brain development in a human being. But Pasca, who is also the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program, pioneered a technology that makes detailed exploration of the developing human brain possible. With special laboratory glassware; a combination of growth factors (substances that stimulate cell growth) and nutrients; and human induced pluripotent stem cells — or iPS cells, which can be generated from a simple skin biopsy — he can generate small clumps of neural tissue whose anatomical architecture and function closely resemble part of the brain, such as the human cerebral cortex. Pasca calls these clumps cortical organoids.

Adjusting the nutrients and growth factors in which iPS cells are bathed, Pasca has shown, generates organoids approximating another brain structure called the subpallium. Located deeper in the forebrain than the cortex, the subpallium plays a key role during fetal and infantile development: It produces inhibitory neurons, known as interneurons, that migrate to the cortex and elsewhere and join up with excitatory neurons to form functioning circuits capable of complex signal generation.

By placing subpallial organoids next to cortical organoids and waiting for several days, Pasca was able to observe, for the first time, how these two structures fuse together to form what he calls “assembloids” and to watch interneurons migrate from the subpallium to the cortex and hook up with excitatory neurons there.

In the new study, Pasca and his colleagues paired this cutting-edge technology with another: CRISPR.

CRISPR employs a molecular scissors and a molecular bloodhound. This enables researchers to snip out specific DNA sequences at will, so they can knock selected genes out of the genome and see what happens.

Pasca and his colleagues narrowed the 661 neurodevelopmental-disorder-associated genes on their list down to 425 that are activated in interneurons. They created iPS cells that when differentiated into multi-celled organoids fluoresce only in those cells that had become interneurons. This way, they could generate subpallial organoids in which they’d be able to distinguish interneurons from all the other brain-cell types the subpallium produces.

They infected thousands of these cells — which had also been bioengineered to carry a gene whose protein product was the molecular scissors of CRISPR — with CRISPR “bloodhounds”: small strips of nucleic acids that are complementary to portions of one or another of the 425 neurodevelopmental-disorder-associated genes of interest. Wherever such a strip affixed itself to a gene, the CRISPR “scissors,” an enzyme, would excise the DNA bound by the strip.

Tossing enough of these bloodhounds into a large enough pool of these cells made it statistically likely that each of the 425 suspect genes would get snipped out in at least hundreds of cells in the pool.

From those iPS cells, the researchers generated subpallial organoids. Some showed no fluorescence at all after 44 days in a dish, indicating their failure to generate interneurons. By sequencing the genomes of these organoids, the researchers could tell which gene had been disabled by the CRISPR scissors, resulting in defective interneuron generation. They identified 13 such genes.

To hunt for genes affecting interneuron migration, Pasca’s team placed subpallial organoids capable of generating interneurons beside healthy cortical organoids in numerous lab dishes. The two types of organoids in each dish fused to form assembloids. After about 30 days of organoid cohabitation, the researchers pulled out about 1,000 assembloids from different dishes and cut each of them apart at the fusion junction. Then they compared the fluorescing interneurons in each assembloid’s subpallial section with those that had crossed the finish line into that assembloid’s cortical section.

By sequencing the genomes of cells, the scientists could pinpoint genes in which a targeted deletion had impaired migration. They found 33 of them.

“The identification of 46 genes — more than 10% of all known neurodevelopmental-disorder-associated genes— whose dysfunction impairs interneuron development points to a subgroup of neurodevelopmental disorders that are characterized by inadequate inhibition of excitatory cortical neurons,” Pasca said.

Some of these genes have been previously uncharacterized, and their function unsuspected, Pasca said.

But other genes have been identified in other studies. “This was a comfort factor,” Pasca said. “It meant we weren’t insane — this approach works.”

Researchers from the University of California, San Francisco, contributed to the work.

The study was funded by the Stanford Brain Organogenesis Program in the Wu Tsai Neuroscience institute and Bio-X, Kwan Funds, Senkut Funds, the Ludwig Foundation, the Mann Foundation, the Chan Zuckerberg Initiative, CZ BioHub, and the New York Stem Cell Foundation.

# # #


About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit




Powering the quantum revolution: Quantum engines on the horizon

Powering the quantum revolution: Quantum engines on the horizon
Quantum mechanics is a branch of physics that explores the properties and interactions of iparticles at very small scale, such as atoms and molecules. This has led to the development of new technologies that are more powerful and efficient compared to their conventional counterparts, causing breakthroughs in areas such as computing, communication, and energy.   At the Okinawa Institute of Science and Technology (OIST), researchers at the Quantum Systems Unit have collaborated with scientists from the University ...

New proof for black hole spin

New proof for black hole spin
The supermassive black hole at the heart of galaxy M87, made famous by the first picture of a black hole shadow, has yielded another first: the jet shooting out from the black hole has been confirmed to wobble, providing direct proof that the black hole is spinning. Super massive black holes, monsters up to billions of times heavier than the Sun that eat everything around them including light, are difficult to study because no information can escape from within. Theoretically, there are very few properties that we can even hope to measure. One property that might possibly be observed is spin, but due to the difficulties involved there have been no direct ...

Monitoring of radio galaxy M87 confirms black hole spin

Monitoring of radio galaxy M87 confirms black hole spin
The nearby radio galaxy M87, located 55 million light-years from the Earth and harboring a black hole 6.5 billion times more massive than the Sun, exhibits an oscillating jet that swings up and down with an amplitude of about 10 degrees, confirming the black hole's spin. The study, which was headed by Chinese researcher Dr. CUI Yuzhu and published in Nature on Sept. 27, was conducted by an international team using a global network of radio telescopes. Through extensive analysis of telescope data from 2000­–2022, the research team revealed a recurring 11-year cycle in the precessional motion of the jet base, as predicted ...

Desalination system could produce freshwater that is cheaper than tap water

Desalination system could produce freshwater that is cheaper than tap water
Engineers at MIT and in China are aiming to turn seawater into drinking water with a completely passive device that is inspired by the ocean, and powered by the sun.  In a paper appearing today in the journal Joule, the team outlines the design for a new solar desalination system that takes in saltwater and heats it with natural sunlight.  The configuration of the device allows water to circulate in swirling eddies, in a manner similar to the much larger “thermohaline” circulation of the ocean. This circulation, ...

Protecting lands slows biodiversity loss among vertebrates by five times

Protecting lands slows biodiversity loss among vertebrates by five times
Protecting large swaths of Earth’s land can help stem the tide of biodiversity loss—including for vertebrates like amphibians, reptiles, mammals and birds, according to a new study published in Nature Sept. 27. The study, led by the Smithsonian Environmental Research Center (SERC) and Conservation International, emphasizes the importance of proper governance for the success of protected lands, and offers much-needed support for the United Nations’ “30 by 30” initiative to conserve the ...

How an audience changes a songbird’s brain

How an audience changes a songbird’s brain
NEW YORK, NY — His mind might have been set on finding water or on perfecting a song he learned as a chick from his dad. But all of that gets pushed down the to-do list for an adult male zebra finch when he notices a female has drawn nigh.    “The males stop worrying about anything else and, for the first time, we have found signs of that re-prioritization in the behavior of specific brain cells,” said Vikram Gadagkar, PhD, a principal investigator at Columbia’s Zuckerman Institute and a co-first author, along with graduate student Andrea Roeser of Cornell ...

Organic lasers have a bright future

Scientists at St Andrews are leading a significant breakthrough in a decades-long challenge to develop compact laser technology. Lasers are used across the world for a huge range of applications in communications, medicine, surveying, manufacturing and measurement.  They are used to transmit information across the internet, for medical treatments, and even in the face scanner on phones.  Most of these lasers are made from rigid, brittle, semiconductor crystals such as gallium arsenide. Organic semiconductors are a newer class of electronic material. Flexible, based on carbon and emitting visible ...

Women’s mood worsens during ‘pill pause’ period of monthly contraceptive pill cycle

Type of work: peer-reviewed/observational study/people Barcelona: Most contraceptive pills are based on a cycle of taking the pill for 21 days, and then stopping the pill for 7 days. Now researchers have found that women’s mood worsens during the 7 pill-free days. This work will be presented at the ECNP congress in Barcelona on 8th October, after recent publication (see notes). Lead researcher, Professor Belinda Angela Pletzer (of Paris Lodron University, Salzburg, Austria) said “We investigated women’s mental health during the pill pause in long-term pill users: since they are long-term ...

Teams investigate material degradation process of carbon-based catalyst

Teams investigate material degradation process of carbon-based catalyst
Although a plethora of carbon-based catalysts have been developed to promote oxygen reduction reaction (ORR) in different electrochemical systems, the degradation process of those catalysts remains obscure to date. During certain steps of the ORR on a catalyst's surface in electrochemical systems, hydrogen peroxide (H2O2) is generated. This compound can be detrimental to the catalyst itself because the highly oxidative species produced from H2O2 can attack different moieties of the catalyst, leading to the degradation of its chemical structure. A team of researchers has elucidated how H2O2 affects the degradation of a carbon-based catalyst named N-G/MOF. This catalyst ...

Team examines importance of zeolite in catalysts for syngas conversion

Team examines importance of zeolite in catalysts for syngas conversion
The fuels used today depend heavily on petroleum. As the demand grows, scientists are looking for ways to produce fuels that do not require petroleum. A research team set out to examine the role of zeolites in the conversion of synthetic gas to fuels. Wanting to better understand how zeolites regulate the reaction pathways, they reviewed the most recent advancements in synthetic gas conversion with catalysts containing zeolites.   Their review paper is published in the journal Carbon Future on July 28, 2023.   As an alternative ...


Artificial intelligence outperforms clinical tests at predicting progress of Alzheimer’s disease

ReMDO announces inaugural Piedmont Triad Regenerative Medicine Engine Ecosystem Summit in Winston-Salem, North Carolina

HarvestHub app tackles supply chain, food insecurity issues

Mathematics outreach program awarded Dolciani grant

Groundbreaking study reveals insights into Alzheimer's disease mechanisms through novel hydrogel matrix

Study examines urban forests across the United States

2023 Rolling Hills Estates landslide likely began the winter before

Rutgers researchers spot potential hazard with private well water treatment

When to trust an AI model

Research shows gamified investment sites have risks for novice investors

Specially equipped natural killer cells show effectiveness against the most common form of ovarian cancer

Entering the golden age for antibody-drug conjugates in gynecologic cancer

Judge: Texas university must release records on research study that resulted in deaths of dozens of animals

UMass Amherst food scientist rises to the challenge of giving marbled fatty feel and taste to plant-based meat

Complex impact of large wildfires on ozone layer dynamics unveiled by new study

Brain inflammation triggers muscle weakness after infections

Research alert: All stem cell therapies are not created equal

Complex impact of large wildfires on ozone layer dynamics

AI found to boost individual creativity – at the expense of less varied content

Texas A&M research collaboration uncovers how domestic rabbits become feral in the wild

Scientists find new way global air churn makes particles

Researchers discover a new neural biomarker for OCD

Vivid portrait of interacting galaxies marks Webb’s second anniversary

UMass Amherst awarded $2.1 million to advance the science of engagement in community-academic research partnerships

With gene editing, mice with a form of inherited deafness can hear again

Sant Pau researchers discover a new gene that causes ALS

Synthetic biology reveals the secrets of life without oxygen

UC3M student startup, Solaris Vita, awarded in Europe's largest entrepreneurship competition

How plant cold specialists can adapt to the environment

Biomarkers reveal how patients with glaucoma may respond to treatment

[] Impact of genes linked to neurodevelopmental diseases found in Stanford Medicine-led study
Jumble of autism genes categorized